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Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial.
Lancet Neurol. 2018 09; 17(9):749-759.LN

Abstract

BACKGROUND

Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment.

METHODS

In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121).

FINDINGS

Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events.

INTERPRETATION

Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy.

FUNDING

Britannia Pharmaceuticals.

Authors+Show Affiliations

Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria. Electronic address: regina.katzenschlager@wienkav.at.Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.Université de Toulouse 3, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Centre d'Investigation Clinique CIC1436, Réseau Ns-Park, French Clinical Research Infrastructure Network, Centre Expert Parkinson de Toulouse, Centre d'Excellence en Maladies Neuro-dégénératives NeuroToul, Department of Clinical Pharmacology and Neurosciences, Toulouse University Hospital, Toulouse, France.Department of Neurosurgery, University Medical Center Goettingen, and Centre of Parkinsonism and Movement Disorders, Elena Hospital, Kassel, Germany.Department of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany; Christian-Albrechts University, Kiel, Germany.National Parkinson Foundation Centre of Excellence, Kings College Hospital, London, UK.Movement Disorder Clinic, Bispebjerg Hospital, Copenhagen, Denmark.Department of Neurology, University Medical Centre, Groningen, Netherlands.Britannia Pharmaceuticals, Reading, UK.Britannia Pharmaceuticals, Reading, UK.Sigma Statistical Services, Balmullo, UK.University College London Institute of Neurology, London, UK.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30055903

Citation

Katzenschlager, Regina, et al. "Apomorphine Subcutaneous Infusion in Patients With Parkinson's Disease With Persistent Motor Fluctuations (TOLEDO): a Multicentre, Double-blind, Randomised, Placebo-controlled Trial." The Lancet. Neurology, vol. 17, no. 9, 2018, pp. 749-759.
Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.
Katzenschlager, R., Poewe, W., Rascol, O., Trenkwalder, C., Deuschl, G., Chaudhuri, K. R., Henriksen, T., van Laar, T., Spivey, K., Vel, S., Staines, H., & Lees, A. (2018). Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet. Neurology, 17(9), 749-759. https://doi.org/10.1016/S1474-4422(18)30239-4
Katzenschlager R, et al. Apomorphine Subcutaneous Infusion in Patients With Parkinson's Disease With Persistent Motor Fluctuations (TOLEDO): a Multicentre, Double-blind, Randomised, Placebo-controlled Trial. Lancet Neurol. 2018;17(9):749-759. PubMed PMID: 30055903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. AU - Katzenschlager,Regina, AU - Poewe,Werner, AU - Rascol,Olivier, AU - Trenkwalder,Claudia, AU - Deuschl,Günther, AU - Chaudhuri,K Ray, AU - Henriksen,Tove, AU - van Laar,Teus, AU - Spivey,Kevin, AU - Vel,Senthil, AU - Staines,Harry, AU - Lees,Andrew, Y1 - 2018/07/25/ PY - 2018/05/01/received PY - 2018/05/31/revised PY - 2018/06/07/accepted PY - 2018/7/30/pubmed PY - 2019/5/3/medline PY - 2018/7/30/entrez SP - 749 EP - 759 JF - The Lancet. Neurology JO - Lancet Neurol VL - 17 IS - 9 N2 - BACKGROUND: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment. METHODS: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121). FINDINGS: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events. INTERPRETATION: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy. FUNDING: Britannia Pharmaceuticals. SN - 1474-4465 UR - https://www.unboundmedicine.com/medline/citation/30055903/Apomorphine_subcutaneous_infusion_in_patients_with_Parkinson's_disease_with_persistent_motor_fluctuations__TOLEDO_:_a_multicentre_double_blind_randomised_placebo_controlled_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1474-4422(18)30239-4 DB - PRIME DP - Unbound Medicine ER -